The molecular mechanism of cell adhesion by classical cadherins is now understood at an atomic level of[unreadable] detail. However, the basis of desmosomal cadherin function has not yet been determined. This Pilot and[unreadable] Feasibility project is focused on determining the first high-resolution structures of desmosomal cadherins in[unreadable] order to determine the detailed molecular.basis of their cell adhesive function. The cadherin family is[unreadable] characterized by their extracellular cadherin repeat domains (EC1-EC5). It is known that the adhesive[unreadable] function of the cadherin extracellular region is dependent upon the binding of calcium ions between each of[unreadable] these repeat domains which leads to the rigidification of the entire region, however, the specific interfaces[unreadable] and interactions responsible for adhesion are not clearly understood. Some light was shed on this issue[unreadable] recently when the crystal structure of the extracellular domain of C-cadherin was solved by our group. This[unreadable] structure revealed that binding between C-cadherins on opposing cell surfaces most likely occurs when a[unreadable] conserved tryptophan (Trp2) residue of a C-cadherin on one cell intercalates into a hydrophobic pocket,[unreadable] containing highly conserved R-A-L residues, of a C-cadherin on an opposing cell. Further, it was noted that[unreadable] C-cadherins on the same cell surface may interact via a similar mechanism to promote molecular clustering[unreadable] thereby allowing for enhanced adhesion between cells. Both the Trp2 residue and the hydrophobic binding[unreadable] pocket are conserved in desmosomal cadherins, therefore, it seems likely that desmogleins and[unreadable] desmocollins may interact via this same mechanism. However, to date no crystal structure for any of the[unreadable] desmosomal cadherins has been solved. This led us to hypothesize: What is the structure of the adhesive[unreadable] interface of a desmosomal cadherin? How do the adhesive interfaces of desmosomal cadherins interact to[unreadable] contribute to the formation of desmosomes? In order to gain some understanding about the structure of the[unreadable] extracellular domain of desmosomal cadherins, we have embarked on a collaborative effort with Dr. Angela[unreadable] Christiano in the Department of Dermatology at Columbia University to crystallize the extracellular domain of[unreadable] human desmogleins. The goal of this Pilot and Feasibility study is to understand the detailed molecular[unreadable] mechanisms of cadherin function in desmosome intercellular junctions.[unreadable] Dr. Shapiro qualifies under eligibility Category #2 in the Guidelines as an Established Investigator with no[unreadable] previous work in research related to the SDRC. He is an internationally renowned structural biologist who[unreadable] has resolved the structure of many classical cadherins. In this proposal, he will turn his attention to the[unreadable] desmosomal cadherins, central players in skin biology. Dr. Shapiro's P&F study utilizes Cores C and D.